This application is based on Japanese Patent Applications 2000-103298 filed on Apr. 5, 2000, the entire contents of which is incorporated herein by reference.
1. Field of the Invention
The present invention relates to a transdermal administrating device, and more particularly, to a transdermal administrating device which allows an ionic agent to permeate from a predetermined site on the surface of skin into subcutaneous tissue by using the principle of iontophoresis.
2. Description of the Related Art
Iontophoresis is a transdermal drug delivery technique which permits drug ions to permeate into subcutaneous tissue while drifting them under a potential applied on a skin medium by using electrophoretic phenomenon.
For example, a set of electrodes are placed being in contact with the surface of skin and spaced from each other.
One of the electrodes of the set is called an active electrode. The active electrode contains a conductive electrode layer and a conductive matrix layer, i.e., a drug reserving and releasing layer (which is referred to as a conductive drug layer hereinafter) having dispersed ionic drug(s) which is applied on one surface of the conductive electrode layer.
The active electrode should be disposed in such a manner as the conductive drug layer is in contact with skin.
The other electrode has usually no conductive drug layer on the bottom surface thereof. This electrode is referred to as an inert electrode.
In the present specification, such a condition as the electrode or the conductive drug layer being placed in contact with skin is referred to as xe2x80x9cdermocontactxe2x80x9d.
A power supply is connected between the active electrode and the inert electrode. Polarity of the power supply to be connected to each of the electrodes is selected so that the drug ions are drifted from the active electrode to the inert electrode in the subcutaneous tissue. Application of power between the electrodes produce an electric field in the non-dermocontact region of the subcutaneous tissue and the field allows the drug ions contained in the conductive drug layer disposed in the active electrode to be withdrawn into the subcutaneous tissue. The drug ions withdrawn into the subcutaneous tissue may enter into, e.g. blood vessels.
The transdermal drug delivery process by iontophoresis makes it possible to miniaturize a drug dispenser itself as opposed to the conventional administrating processes such as ordinary dropping. Miniaturization of devices permits patients to carry them, thereby reducing a load in daily life.
The transdermal drug delivery process by iontophoresis can reduce a burden to patients and enhance a quality of life of patients. Therefore, it is an excellent drug delivery system. The power supply may be a small dry battery based on portability.
Drugs having a narrow acceptable range of drug concentration, such as hormone drug, anti-cancer drugs, anaesthetics and the like are administrated into a blood vessel by venous penetration. In this case, the drug-concentration in blood is controlled by monitoring a dosage amount into a blood vessel to adjust the dropping rate of the drug(s).
If iontophoreisis, which is a non-invasive drug delivery method, is employed, it is difficult to appropriately monitor the amount of drug to be dispensed into blood vessels. Therefore, iontophresis has been less applicable to administration of drugs having a narrow acceptable range of blood drug-concentration.
An object of the present invention is to provide a novel transdermal drug delivery technique, which can be applied to administration of various drugs including those having a narrow acceptable range of blood drug concentration in blood.
According to an aspect of the present invention, there is provided a transdermal administrating device comprising; an active electrode having a conductive electrode layer and a conductive drug layer applied on one surface of said conductive electrode layer, said conductive drug layer being placed in contact with skin; an inert electrode made of electro conductive material which is placed in contact with skin and spaced a distance from said active electrode; a means of applying a variable voltage across said active electrode and said inert electrode; a set of first and second conductive electrode layers, each made of a material having a different standard single electrode potential, which are placed in contact with skin and spaced a distance from each other; a controller connected to a non-dermocontact region between said first conductive electrode layer and said second conductive electrode layer and measuring an internal resistance of subcutaneous tissue between said first electrode layer and said second electrode layer and controlling an electric current passing through the subcutaneous tissue between said active electrode and said inert electrode based on the measured internal resistance; and a dermocontact means for keeping said active electrode, said inert electrode, and said first and second electrodes in contact with skin.
According to another aspect of the present invention, there is provided a process for drug delivery comprising steps consisting of (a) attaching on the surface of skin an active electrode having a conductive electrode layer and a conductive drug layer applied on one surface of said conductive electrode layer, said conductive drug layer being placed in contact with skin; an inert conductive electrode which is placed in contact with skin and spaced a distance from said active electrode; and a set of first and second conductive electrode layers, each made of a material having a different standard single electrode potential, which are placed in contact with skin and spaced a distance from each other, (b) detecting an electric current passing through an subcutaneous tissue between said first conductive electrode layer and said second conductive electrode layer to evaluate an internal resistance of the subcutaneous tissue, (c) determining an internal resistance for keeping a concentration of the drug ions in blood at a desired level based on a predetermined calibration curve which shows a relationship between the concentration of the drug ions released from said conductive drug layer and the internal resistance, and (d) controlling said electric current passing through the subcutaneous tissue between said active electrode and said inert electrode so as to maintain said internal resistance obtained in the step (c).
Iontophoresis can be carried out by placing both the conductive drug layer attached intimately on the bottom surface of the active electrode and the inert electrode in contact with skin apart from each other and applying a monopolar potential in the non-dermocontact region between the active electrode and the inert electrode to cause a drift of the effective drug component(s) from the conductive drug layer into the subcutaneous tissue. A chemical cell is formed among a skin and the electrodes when simultaneously the positive electrode and the negative electrode, each made of a conductive material having a different standard single electrode potential, are separately placed in contact with skin. Then, by measuring and calculating a variation in an internal loss of the chemical cell, a variation in the concentration of the effective component(s) permeated into the subcutaneous tissue can be obtained. This result is fed back to the control of the single electrode potential or the flowing current so as to control the drug concentration in blood.
For iontophoresis, the active electrode and the inert electrode are used. For the detection of the internal loss of the chemical cell, a set of the first conductive electrode layer and the second conductive electrode layer each made of an electrically conductive material having a different standard single electrode potential is used as a sensor. The active electrode and the inert electrode may be served as a set of conductive electrode layers, too.
In order to maintain the chemical stability of the surface of electrode, there may be employed an device structure where the dermocontact sides of the inert electrode and (or) the drug-contact side of the active electrode are coated with materials different from those of the inert electrode and the active electrode.
It is possible to control the monopolar potential applied across the active electrode and the inert electrode by the DC power supply in connect with the non-dermocontact region between the active electrode and the inert electrode, which power supply is for applying a bias voltage. Alternatively, the control of the flowing current may be achieved by controlling the value of an electric resistance interposed between the active electrode and the inert electrode.
It is contemplated to use a combination of two electrically conductive materials having different single electrode potentials where among them, the one having a lower single electrode potential may be of n-type semiconductor. Employing the n-type semiconductor negative electrode can sustain stably the electrode reaction because a Schottky potential barrier formed on the dermocontact surface prevents anions from invading into the negative electrode. In addition, the hole injection from the negative electrode into the subcutaneous tissue reduces alkalization of the skin resulting in an reduction in skin damage.
The present invention makes advantageously it possible to control easily the drug concentration in blood, to enhance the quality of life of patients, and moreover to add to a variety of transdermally administrable drugs.